A system is provided for withdrawing small amounts of body fluid from an animal or human. The system includes a holder and a disposable lancing unit attached to the holder. The lancing unit also includes an open capillary channel for transporting the body fluid and piercing the skin.

The present invention relates to the field of body fluid analyses in order to make a diagnosis or to monitor the concentration of metabolic parameters such as the blood glucose concentration.
The invention concerns a system for withdrawing small amounts of body fluid comprising a drive unit with a holding device for a disposable lancing unit which has a holding area and a capillary structure connected to the holding area. The capillary structure has at least one capillary channel and a tip for piercing the skin which faces away from the holding device. At least a part of the longitudinal extension of the capillary structure is open towards the outside.
Systems for withdrawing body fluids are already known in the prior art in which the body fluid is taken up into a disposable element. Blood collection and analytical systems are known from the document EP 0 199 484 which comprise a disposable unit with a capillary to collect body fluid and transport the body fluid into a detection area. The further development of this concept is described in WO 97/42888. The arrangement described herein is particularly suitable for collecting relatively small amounts of body fluids which is primarily accomplished by pressing a ring onto the area surrounding a collection site and a pumping movement. A system for analysis based on small amounts of interstitial fluid is known from EP 0 723 418. For this purpose a very thin closed hollow needle is inserted into the dermis and interstitial fluid is conveyed through the needle to a test zone by applying pressure to the area surrounding the puncture site. A highly miniaturized arrangement which also utilizes a closed needle to withdraw body fluid is known from U.S. Pat. No. 5,801,057. A particular advantage of this arrangement is the extremely thin needle which can be inserted at least into the arm region of a patient without essentially any pain.
Whereas the arrangement described in U.S. Pat. No. 5,801,057 already fulfils numerous practical requirements, some features are in need of improvement. A general problem with the sampling devices according to the previously mentioned document is to manufacture the hollow needle cost-effectively and as small as possible. Miniaturization which is in particular desirable with regard to minimizing the pain caused by the lancing process and minimizing the size of the puncture wound results in high manufacturing costs for the very thin closed needles and there are additional fundamental feasibility problems.
According to the present invention the requirements for systems for withdrawing small amounts of body fluids are met using needles with an open capillary structure instead of the closed needle designs known in the prior art. This not only results in considerable advantages for the manufacturing process by making it possible to manufacture the sampling system in a cost-effective and simple manner, but it also results in major advantages in the collection of body fluids since this does not only occur through the cannula tip of the hollow needle as in the case of closed needle designs but also through the open area of the capillary structure. Moreover one can also utilize the advantage that the open channel area of the needle, even when it is still inserted, is able to collect blood from the skin surface and transport it to a detection zone.
One particular field of application of systems for withdrawing small amounts of body fluid is the so-called spot-monitoring in which the concentration of particular analytes present in the body fluids is determined at a particular time. Such measurements can be carried out repeatedly at time intervals in order to monitor a change of the analyte concentration. Such an analysis using disposable test elements has proven to be particularly advantageous especially in the field of blood sugar measurement by diabetics. If excessively high blood sugar values (hyperglycaemia) occur in a diabetic over a certain period of time, this can lead to serious long-term damage such as blindness and gangrene. If, on the other hand, a diabetic falls into a state of hypoglycaemia because he has for example injected too large a dose of insulin, this can become life-threatening if the diabetic falls into a so-called hypoglycaemic shock. In contrast a regular control of the blood sugar level enables the diabetic to avoid hyperglycaemic and hypoglycaemic states and also permanently learn how to coordinate his eating habits, bodily activity and insulin medication. In addition to improving and maintaining the health of diabetics, regular blood sugar monitoring also has considerable overall economic advantages since the high costs for secondary diseases can be avoided. The reasons which prevent a more widespread and consequent use of blood sugar monitoring are primarily the pain caused by the required body fluid collection and the extensive handling steps of the common systems in the market. With the current widely used systems the diabetic or medical staff must firstly obtain a drop of blood which is usually from the finger pad. If this is to be carried out with as little pain as possible, so-called lancing devices are used. A lancing device must be firstly loaded with a lancet, tensioned, placed on the body surface and triggered. After the lancing process the user has to knead his finger in order to convey a drop of blood out of the puncture wound which should be as small as possible. Before this procedure the diabetic has to already place a test strip in a blood sugar measuring instrument and activate it. The drop of blood can now be applied to the test strip and after for example 10 seconds a blood sugar measurement is available. The user now has to also dispose of the spent lancet and test strip. The present invention enables the process of blood sugar measurement to be greatly simplified by providing a so-called integrated system in which only one (disposable) unit carries out the lancing, sampling and analytical reaction.
A system according to the invention serves to withdraw small amounts of body fluid. In this context body fluids are understood in particular as blood, interstitial fluid and mixtures of these body fluids. Whereas in conventional systems for blood collection this is usually carried out on the finger pad, the collection system according to the invention can also be used to withdraw blood from other sites on the body such as the forearm.
A disposable lancing unit for withdrawing small amounts of body fluid according to the invention has a holding area which is connected to the proximal end of an elongate capillary structure having at least one capillary channel to transport body fluid. The distal end of the capillary structure is suitable for piercing skin and at least a part of the capillary structure is open to the outside along its longitudinal extension. A capillary structure is understood within the scope of the invention as a body which transports body fluid as a result of capillary forces towards the proximal end of the capillary structure when the distal area is contacted with body fluid. With regard to this function the capillary structure according to the invention is similar to the hollow needles described in U.S. Pat. No. 5,801,057 and EP 0 723 418. However, an important difference is that at least one area which comprises at least part of the longitudinal extension of the capillary structure is open to the outside. The longitudinal extension of the capillary structure extends from the proximal end which is connected to the holding area to the distal area which is intended to be inserted into the skin. The hollow needles of the prior art only have an opening at their outermost distal end through which body fluid can enter. In contrast the capillary structure according to the invention can take up body fluid over a much larger part of its longitudinal extension. As a rule the length of the region of capillary structure which is open to the outside is more than 10% of the longitudinal dimension of the capillary structure and preferably more than 50% of the longitudinal dimension. It is particularly advantageous for the manufacturing process when the capillary structure is open to the outside along its entire longitudinal dimension.
Conventional hollow needles are manufactured in the prior art by drawing out thicker tubes. It is consequently very laborious and costly to manufacture very thin hollow needles of for example less than 0.3 mm outer diameter. In contrast U.S. Pat. No. 5,801,057 proposes a different method. A first body which has a needle area with a channel and a measuring chamber which is integrally connected to the needle is etched from silicon, the measuring chamber and channel are subsequently sealed with a layer in the area of the needle. The two bodies are for example connected by anodic bonding. The high degree of miniaturization of the blood sampling device and the bonding step in the process result in very high manufacturing costs. Furthermore, the arrangement that is formed according to the previously mentioned documents of the prior art can also only take up liquid via the tip area of the needle. According to the invention it was found that it is possible to also achieve an efficient uptake of liquid when an open capillary is present. Examples of such open capillaries are described in the following:
Open capillaries can be manufactured by photolithographic methods like those described in the document U.S. Pat. No. 5,801,057 and which are known from the field of semiconductor technology. It is also possible to provide channels, grooves etc. which are open to the outside in solid needles by milling, etching and suchlike. Such depressions lead from the tip or at least from a region adjoining the tip to the proximal end of the needle which is connected to the holding device. These depressions or capillaries do not necessarily have to run in straight lines, but can also for example be arranged in spirals, meanders etc. It is important that liquid is transported through the capillaries from the distal area of the needle into the proximal area. The cross-section of the capillaries can for example be V-shaped, semi-circular or also rectangular. It is important that a part of the cross-section is open to the outside so that fluid can penetrate into the capillary channel through the external peripheral surface of the needle.
In addition to the already mentioned methods for incorporating capillary channels into rod-shaped bodies, it is also possible to generate the capillary channels by assembling bodies. Thus it is for example possible to fasten two or more solid needles together for example by welding such that the contact areas of the solid needles form capillary channels. In a corresponding manner it is also possible to twist wires together in the form of a stranded wire such that numerous contact areas are formed which generate the capillary channels.
The capillary channels which are present in the capillary structure typically have a greater depth than width. The ratio of depth to width (generally referred to as aspect ratio) is preferably 2 to 5. The cross-section of the capillary channel is typically larger than 2500 .mu.m.sup.2 and less than 1 mm.sup.2. As already stated above it is advantageous that the capillary channels are accessible to the outside such that they can also take up body fluid while the capillary structure is inserted into tissue. In order to achieve a good uptake of body fluid the area of the capillary structure that is open to the outside should have a length of 1 mm or more.
The holding area adjoins the proximal part of the capillary structure. The holding area and capillary structure can be formed as one piece (monolithic) as well as be separate parts which are connected together by glueing, welding, press fitting or suchlike.
Monolithic structures can be generated particularly advantageously from semiconductors using the known manufacturing processes for semiconductors. This can result in a very high degree of miniaturization. In contrast the manufacturing costs may be more favourable when the lancing device is manufactured from a separate holding area and a separate capillary structure. A lancing device made of separate elements can for example be formed from a metallic capillary structure and a holding area made of plastic.
The proximal area of the capillary structure or the holding area of a lancing device according to the invention can have an evaluation zone. If the analyte concentration is for example evaluated by means of infrared spectroscopy, the detection zone does not have to contain further reagents to enable the analyte to be determined. Since the materials for the capillary structure and the holding area are usually impermeable to infrared light, analysis by reflection spectroscopy is preferred. For this purpose the evaluation zone can preferably reflect IR light which is usually the case to an adequate extent with metal surfaces. Plastics can for example be made to reflect IR light by vapour depositing or sputtering gold or aluminium. (Alternatively optically transparent windows can also be integrated).
However, in the preferred case the lancing unit has a detection zone in which a reagent is located which undergoes a detectable change on contact with an analyte to be detected in the sample of body fluid. Typical reagents for detecting glucose are based for example on glucose oxidase in conjunction with a chromogenic redox system. Reagents are well known in the prior art for an optical evaluation which form a colour with glucose from the body fluid. Furthermore reagents are also known from the field of blood sugar test strips which allow an electrochemical detection of an analyte. Since such detection systems are also well-known from the prior art they are not described in more detail herein.
The said reagent systems can be arranged in the proximal area of the capillary structure, but since there are no particularly convenient possibilities for immobilizing and evaluating the reagents in this area, it is preferable to place the reagents in the holding area. In order to wet the reagents with body fluid, the reagent either directly adjoins the capillary structure and can take up body fluid by its own capillary forces or a fluid connection (e.g. connecting channel, fleece etc.) can be provided between the capillary structure and the detection zone through which the body fluid can pass from the capillary structure into the detection zone. The lancing unit can for example be designed such that a capillary channel of the capillary structure is extended into the holding area and a reagent in the area of the holding area can be applied directly to the capillary channel which extends into this area. The reagent mixtures that are used are usually in a solid state and, due to their constituents (e.g. aluminium oxide, kieselguhr and suchlike), have such a high capillarity that they can take up body fluid from the capillary channel.
The shape of the holding area is relatively uncritical. It can for example be in the form of a small cube which has a depression to receive the reagent mixture. Special measures are usually not necessary to mount the lancing unit in a drive unit, or designs can be used that are known for disposable lancets of conventional blood sampling systems. For example the holding area can have tapers into which spring elements of a holder of the drive unit engage in order to hold the lancing unit. The lancing unit is advantageously positioned within the holder in such a manner (for example by pressing the end of the lancing unit facing away from the tip against a stop) that it allows a good control of the piercing depth of the lancing unit. Reference is made to the document EP B 0 565 970 with regard to such a holder and the interaction between the holder and the disposable lancing unit.
In a system for withdrawing small amounts of body fluids it may be advantageous to integrate a detection unit. If a lancing unit containing a reagent is used which changes colour or forms a colour when an analyte is present, the system can have an optical detection unit comprising a light source and a detector to detect transmitted or reflected light. If electrochemical detection is used, the system can have electrodes which contact the reagent of the lancing unit or the contacts of the lancing unit which in turn contact the reagent. For the evaluation the system can have the electronic devices known in the prior art in order to determine the concentration of the analyte for example by measuring the so-called Cotrell current. If it is intended to carry out a reagent-free analysis, the system can for example comprise an infrared radiation source and an infrared detector and devices for the spectral resolution of the radiation reflected from the evaluation zone.
The collection system according to the invention additionally has a drive unit which, when activated, moves the holder from a first into a second position such that the lancing unit performs a lancing movement. Such drive units are well-known from the field of blood sampling systems. It can for example contain a spring which is tensioned by the user and drives the lancing unit when it relaxes. A particularly advantageous drive unit is described in EP B 0 565 970.
With the lancing unit according to the invention or the collection system according to the invention, body fluid can be withdrawn while the capillary structure or a part thereof is inserted into the skin (i.e. withdrawal directly from the body or from body fluid emerging from the body on the body surface) or the capillary structure can be retracted from the body after the piercing operation and take up body fluid that emerges from the body surface. A withdrawal in which the capillary structure remains in the body to collect body fluid is especially suitable for sampling from the arm. This is due to the fact that small incisions on the arm close again very rapidly such that no fluid or only very small amounts of fluid emerge after the piercing. On the other hand the sensitivity to pain is much less pronounced on the arm as compared for example to the finger and thus when the capillary structure remains in the body this is not felt to be painful. As described above an advantage of a capillary structure that is open to the outside compared to conventional hollow needles is that fluid can be taken up through the open area whereas the area for taking up liquids by hollow needles is limited to the front end of the needle. The latter is particularly disadvantageous when the needle opening becomes sealed by tissue components during the piercing process such that no liquid or only an inadequate amount can be taken up.
It also has an advantage over conventional hollow needles in the case of a withdrawal in which the capillary structure is retracted from the tissue after the lancing process. As already described capillary structures that are open to the outside can be much more simply and cheaply manufactured than closed hollow needles.
Furthermore a withdrawal process can be carried out with the lancing units according to the invention which is a combination of the previously mentioned processes. In this combination process piercing is firstly carried out, the capillary structure is pulled back over a part of the piercing path and is allowed to reside there for a collection period of several seconds. An advantage of this process is that the retraction of the capillary structure exposes part of the lancing channel such that body fluid can collect in it and can enter from there into the capillary structure.
A further decisive factor which is important for an efficient uptake of body fluid by means of the capillary structure is the wettability of the capillary channels. If capillary structures made of silicon are used, these are usually adequately wettable due to a silicon oxide layer on the surface. If metals are used for the capillary structure, these are often relatively difficult to wet. This can be counteracted by a number of different measures such as silication of the surface. The wettability is usually adequate when the liquid in the capillaries has a concave meniscus which is synonymous with a wetting angle of less than 90°.

System for withdrawing small amounts of body fluid


An active substance matrix patch for controlled delivery of nonsteroidal antirheumatics to the skin, comprising a flexible cover layer and a water insoluble, pressure sensitively adhesive active substance matrix, wherein said adhesive matrix is free from mineral oils and tackifier resins and is composed of

The invention relates to a drug patch system based on synthetic rubbers for delivering at least one nonsteroidal antirheumatic for absorption through the skin over a period of up to 24 h, and to a process for producing it.
Transdermal therapeutic systems (TTS) for delivering active substances through the skin have been known for a long time. The topical application of drugs by way of active substance patch systems offers two main advantages. Firstly, this form of administration produces first order release kinetics of the active substance, thereby enabling a constant level of active substance to be maintained in the body over a very long period. Secondly, the path of uptake through the skin avoids the gastrointestinal tract and also the first liver passage. As a result, selected drugs may be effectively administered in a low dose. This is particularly advantageous when the drug is desired to act locally while avoiding a systemic effect. This is the case, for example, with the treatment of rheumatic joint complaints or muscular inflammation.
One embodiment of such transdermal systems which has been well described in the technical literature is that of matrix systems or monolithic systems in which the drug is incorporated directly into the pressure sensitive adhesive. In the ready-to-apply product, a pressure sensitively adhesive matrix of this kind, comprising active substance, is equipped on one side with a backing impermeable to the active substance, while on the opposite side there is a backing film equipped with a release layer, which is removed prior to application to the skin (klebenanddichten, No. 42, 1998, p. 26 to 30).
A fundamental requirement of a TTS is very good adhesion to skin, which must be maintained over the entire duration of the intended dosing of active substance. A frequently observed side effect, however, is the appearance of skin irritations, which occur in particular when a TTS is applied for a relatively long period, or repeatedly, to the same body region. The principal cause of these irritations are the ingredients of the pressure sensitively adhesive matrix. Painful redetachment of the active substance patch following a prolonged period of wear is a further observation.
Repeated and long-lasting applications of pressure sensitively adhesive systems to the same regions of the human body are encountered above all in the area of ostomy care. In this utility, hydrocolloids have long been used with great success as pressure sensitive adhesives. They consist in principle of a hydrophobic, pressure sensitively adhesive polymer matrix based on synthetic rubbers, dispersed in which matrix there are insoluble hydrophilic fillers based on, for example, alginates, cellulose or pectins. In the development of hydrocolloids for ostomy care, however, the primary requirements are the adhesion properties to wet skin and the ability to absorb liquid.
As long ago as 1967, U.S. Pat. No. 3,339,546 described a hydrocolloid based on polyisobutylenes for use in the oral cavity. A great disadvantage of the early systems was the deficient integrity of the matrices, i.e., the dissolution and breakup of the pressure sensitively adhesive matrix on absorption of relatively large amounts of liquid.
Later developments therefore aimed to solve this problem, and a number of proposed solutions are described in the literature. U.S. Pat. No. 4,393,080, for example, describes a hydrocolloid system based on elastomers, which uses high molecular mass hydrophilic fillers which promote the cohesion of the system even when swollen.
Further patents describe solutions by way of the crosslinking of the elastomer matrix, which may take place either physically or chemically.
Physical crosslinking, for example, may be effected by using phase separating block polymers based on poly(styrene-b-isoprene-b-styrene) (SIS), poly(styrene-b-isoprene-b-styrene) (SBS) or poly[styrene-b-(ethylene-stat.-butylene)-b-styrene] (SEBS). One of the first such systems is described, for example, in DE 28 22 535.
Chemical crosslinking may be effective, for example, by electron beam treatment or xcex3 irradiation of the hydrocolloid matrix. A prerequisite for this is the presence in the pressure sensitively adhesive matrix of a sufficient number of reactive structural elements. This can be achieved, for example, as described in U.S. Pat. No. 4,477,325, by compounding with an ethylene-vinyl acetate copolymer.
Within the abovementioned inventions, although the technical problem of the cohesiveness of swollen hydrocolloids is described and solved, the problem of skin irritation as a result of repeated application is not addressed.
In contrast, WO 98/01167 does deal with skin irritations that may occur. In this case, aloe vera extract is used in order to prevent inflammatory skin changes and infection in the context of ostomy care. The system described, however, merely comprises a low molecular mass polyisobutylene as the polymer framework, and so the above-described problem of the cohesiveness of the hydrocolloid matrix continues to exist. Moreover, the composition described uses tackifier resins, whose allergenic potential is known.
Information regarding the suitability of such a system for the controlled delivery of drugs is present neither in this nor in any other of the abovementioned documents.
Transdermal therapeutic systems are generally applied to healthy, intact skin. In this case in particular it is especially important that the intact skin is not irritated, let alone damaged, by a drug. Furthermore, sufficient cohesiveness is necessary in order to be able to remove the active substance patch without residue after the period of wear is at an end.
Polyisobutylenes have long been used as a framework substance in the compounding of pressure sensitive adhesives. Relative to other known elastomers, synthetic polymers based on isobutylene offer a number of advantages. Owing to their synthetic production, they are free from unwanted ingredients; owing to their complete saturation they are highly stable to oxidation; and their inherent tack can be adjusted depending on molecular weight.
For application to skin in particular, therefore, they are preferred over other elastomers. For example, the allergenic potential of natural rubber, deriving from its natural impurities, is well known. Other synthetic rubbers based on styrene and isoprene and/or butadiene are very oxidation sensitive, necessitating the complicated addition of additives. Their hydrogenated derivatives based on poly[styrene-b-(ethylene-stat-propylene)-b-styrene] (SEPS) or poly[styrene-b-(ethylene-stat-butylene)-b-styrene] (SEBS), although more stable to oxidation, nevertheless lack inherent tack. Because of this, they additionally require compounding with tackifier resins in order to be used as pressure sensitive adhesives, as is described, for example, in EP 0 651 635 B1. These resins are generally very poorly defined mixtures of substances, frequently based on rosin. Consequently, here again an allergenic potential can not be ruled out.
The use of polyisobutylenes for transdermal therapeutic systems was described back in 1983 in DE 33 47 278 and DE 33 47 277. There, however, their use was always described in combination with either olefinic diene rubbers or tackifier resins, which again have the disadvantages described above. The use of amorphous poly-a-olefins as additives is also described, but without elucidating their effect on the overall system. The use of fillers is not mentioned in this description.
The use of PIB for transdermal systems without the addition of tackifier resins is described in U.S. Pat. No. 4,559,222. In that case, however, it is necessary to use very large amounts of mineral oil, the ratio of mineral oil to PIB in accordance with that invention being at least 1. Moreover, the system is restricted to active substances which are of moderate solubility in mineral oil. As a result, there is a further softening effect on the matrix. Fillers used comprise at least 6% by weight of colloidal silica. Regarding this ingredient, it is known that the antiadhesive properties of a release film are significantly disrupted by the use of silica.
WO 96/22083 describes a system for the transdermal administration of nicotine which operates on the basis of polyisobutylene without the addition of mineral oil. In this case, however, the necessary tack of the adhesive composition is achieved through the use of tackifier resins. These have the abovementioned disadvantages with respect to skin compatibility. A plasticizing effect, which has an additional positive effect on the adhesive properties of the matrix, is achieved by way of the active substance which is soluble in the PIB matrix. This compounding principle, however, greatly restricts the selection of active substances which can be administered by way of this matrix.
A system for the transdermal administration of drugs, based on polyisobutylenes without the use either of tackifier resins or of mineral oil, is described by U.S. Pat. No. 5,508,038. The central component for achieving sufficient adhesive properties in this case too, however, is the active substance, which in accordance with that invention must be oily and of ready solubility in the nonpolar matrix. This constitutes a very severe restriction, ruling out the use of nonsteroidal antirheumatics in this context. The system described is free from organic and inorganic fillers.
U.S. Pat. No. 5,508,038 is the only one of the cited publications to address the problem of skin irritation through the possible use of tackifier resins.
The use of amorphous poly-a-olefins in pressure sensitive adhesives in general is known in the literature. U.S. Pat. No. 4,186,258 is one of the first documents which designates the use of this class of substance in the field of hot-melt pressure sensitive adhesives. This document does not state a specific field of use.
U.S. Pat. No. 5,262,216 describes the use of these materials together with tackifier resins as hot-melt pressure sensitive adhesives, specifically for use on self-adhesive labels. Qualities of this class of polymer that are particularly praised here are the outstanding UV and aging resistance. There is no mention of their use on the human body.
WO 98/54268, in contrast, specifically describes the use of amorphous poly-xcex1-olefins for applications on human skin. Moreover, in this case amorphous poly-xcex1-olefins are used in combination with fillers. However, the field of use described is specifically that of wound covering. In this application, a particular feature of amorphous poly-xcex1-olefins is their outstanding radiation resistance, as a result of which, in accordance with that invention, it is possible to produce readily sterilizable woundcare products. Additionally, amorphous poly-xcex1-olefins are used here in combination with tackifier resins. Overall, the aspect of reduced skin irritation is not mentioned. Moreover, WO 98/54268 contains no indications that such a system is suitable for delivering drugs via the human skin. This document completely excludes the field of use of transdermal therapeutic systems.
The systems described to date for the transdermal administration of an active substance do not include organic fillers. However, these fillers in particular are responsible for the kindness to skin of the aforementioned pressure sensitive adhesives for ostomy care. By virtue of these fillers, moisture released by the skin during the period of wear of the patch can be absorbed very effectively. The resulting climate below the patch leads to a marked reduction in the incidence of skin maceration.
An invention of an active substance patch using water swellable fillers is described by EP 0 186 019 A1. In that case, however, the positive influence of the organic filler on the release rate of the active substance is described. The filler content in accordance with that invention is limited to 30% by weight. The aspect of the reduction of skin irritation is not addressed. Moreover, the systems described are realized using tackifier resins.
As remarked above, the realization of pressure sensitive adhesive systems for the transdermal administration of active substances, based on polyisobutyl without either tackifier resins or mineral oil, is described only for those drugs which possess an oily consistency at room temperature and/or which are soluble in the matrix. Consequently, the use of nonsteroidal antirheumatics, such as ibuprofen and ketoprofen, for example, is not possible on the basis of the known formulations, owing to the physical properties of these drugs. None of the tackifier resin free formulations described contains a hydrophilic filler.
It is an object of the present invention to develop, for the purpose of controlled delivery of a drug from the group of the nonsteroidal antirheumatics, a hydrocolloid system which not only possesses excellent cohesiveness but is also composed of components which are particularly kind to the skin and can be realized without any need at all for skin irritant components such as tackifying resins, for example. Furthermore, a production process is planned which operates without any solvent whatsoever, and, furthermore, the abovementioned side effects of a pressure sensitive adhesive for transdermal systemsxe2x80x94skin irritations and painful redetachmentsxe2x80x94are avoided, resulting in a significant increase in wear comfort for the patient.
The object is to provide a matrix system which is based on polyisobutylene and which can be realized in a solvent free production process without conventional tackifier resins and mineral oil.
This object is achieved by an active substance matrix patch as claimed in the main claim. The subclaims relate to advantageous embodiments of the patch of the invention. Furthermore, the invention embraces processes for producing such patches.
The invention accordingly provides an active substance matrix patch for controlled delivery of nonsteroidal antirheumatics to the skin, comprising a flexible cover layer and a water insoluble, pressure sensitively adhesive active substance matrix, said adhesive matrix being free from mineral oils and tackifier resins and being composed of
a) from 25 to 90% by weight of synthetic framework polymers based on polyisobutylene,
b) from 5 to 40% by weight of amorphous poly-a-olefin,
c) from 10 to 60% by weight of an insoluble hydrophilic filler having an average particle size of less than 100 pm, and
d) from 0.001 to 20% by weight of a drug.
In a first advantageous embodiment of the active substance matrix patch, the polyisobutylene is composed of from 5 to 30% by weight of high molecular mass PIB and from 20 to 60% by weight of low molecular mass PIB.
A typical pressure sensitive adhesive of the invention accordingly comprises the following
Optionally, up to 20% by weight of a permeation enhancing auxiliary may also be added.
There follows a more precise definition of the abovementioned formulation constituents:
High molecular mass PIB:
Polyisobutylene having a weight average molecular weight (Mw) of from 500 000 to 1 100 000, preferably between 650 000 and 850 000. Such polymers are available commercially, for example, under the trade name Oppanol B100 (BASF) or Vistanex MM-L80 (Exxon).
Low Molecular Mass PIB:
Polyisobutylene having a weight average molecular weight (Mw) of from 40 000 to 120 000, preferably between 60 000 and 100 000. Such polymers are available commercially, for example, under the trade name Oppanol B15 (BASF) or Vistanex LMMH (Exxon).
Amorphous poly-xcex1-olefin:
Amorphous copolymers based on ethylene and propylene, butylene or 1-hexene. The preferred weight average molecular weight (Mw) is from 5 000 to 100 000, preferably between 10 000 and 30 000. Such polymers are available commercially, for example, under the trade name Eastoflex(copyright) (Eastman) or Vestoplast(copyright) (Hxc3xcls).
Hydrophilic Filler:
Cellulose based hydrophilic particles insoluble in the abovementioned polymer matrix. Preference is given to an average particle size of less than or equal to 100 xcexcm with a surface which is as uniform as possible. Such materials are available commercially, for example, under the trade names Avicel (FMC) and Elcema (Degussa-Hxc3xcls).
The active substance matrix is preferably produced in a process in which all of the components of the pressure sensitively adhesive matrix are homogenized in the melt without the addition of solvent.
With particular preference, all components are processed in a continuous or batchwise process at a temperature below 100xc2x0 C.
The matrix is notable for outstanding adhesion properties on the skin, by easy and painless redetachability, and in particular by its extremely low potential to induce skin irritation. The production process does not use any solvents at all.
If desired, the open adhesive sidexe2x80x94that to be applied to the skinxe2x80x94may be lined with a redetachable, covering protective layer.
As far as the selection of the fillers is concerned, it has surprisingly been found that particularly suitable fillers are those based on cellulose which possess an isotropic form and do not tend to swell on contact with water. Of these, fillers having a particle size of less than or equal to 100 xcexcm are particularly suitable.
The use of hydrophilic fillers in a nonpolar matrix is known in the literature. They are described explicitly for use in transdermal therapeutic systems in EP 0 186 019. In that case, however, they are used only in a concentration of from 3 to 30% by weight, and no details of these fillers are given. Experience shows that systems having a filler content of more than 30% by weight suffer a significant loss of tack and become hard and brittle. In so doing, they lose the fundamental qualities required of a transdermal therapeutic system.
In the context of the present invention, however, it has been possible to show that fillers based on microcrystalline or amorphous cellulose can be used in substantially higher concentrations, without adversely affecting the adhesive properties, when they possess an isotropic form with a particle size of not greater than 100 xcexcm. Larger amounts of fillers are desirable for improving the wear properties, especially in the case of long-lasting and repeated application.
The hydrophilic fillers known from the materials for ostomy care are integrated into the matrix of the invention, which serves to assist in skin compatibility.
The objectivexe2x80x94the topical application of drugs from the group of the nonsteroidal antirheumatics, with or without the assistance of highly skin compatible additivesxe2x80x94may be assisted in the context of the present invention by the addition of permeation enhancing auxiliaries such as, for example, fatty acid esters.
Surprisingly, it is possible to realize the abovementioned requirements in particular by means of a system which besides polyisobutylenes comprises amorphous poly-xcex1-olefins in combination with amorphous or microcrystalline cellulose. The polymer basis of this simple system exclusively comprises synthetic ingredients whose quality can be monitored very effectively. As a result, allergenic reactions can largely be ruled out. The complete absence of poorly defined ingredients such as natural rubber or tackifier resins, for example, leads, as a result, to matrices which are particularly kind to the skin. The adhesive properties of the formulation of the invention, furthermore, can be adjusted very effectively. Moreover, there is no need for additional, stabilizing additives in the system. As already indicated, nonsteroidal antirheumatic topical application systems which are particularly kind to the skin can be realized on the basis of polyisobutylenes using amorphous poly-a-olefins and also cellulose particles as a filler.
The particular advantage of this raw material base lies in the exclusive use of fully saturated synthetic elastomers. These are highly defined and characterized, so making it possible to rule out contamination with accompanying allergenic substances. Because of the high degree of saturation, these polymer are highly stable to oxidation. As a result, there is no need for the extra addition of antioxidants and other stabilizers. The use of such additives, as is necessary when using natural rubber or unsaturated synthetic rubbers, always harbors the danger of skin incompatibility, owing to the chemical structure of the additives most commonly used. In addition, they represent an additional cost factor.
Furthermore, all of the elastomers used possess an inherent tack, depending on the molecular weight. As a result, it is also possible to forego the use of tackifier resins. Tackifier resins are frequently mixtures of substances, prepared on the basis of rosin, which are very poorly defined. A uniform structural formula can be given only in the rarest of cases. This makes it difficult to use tackifier resins as raw materials in drugs requiring approval, as in the present case of the transdermal therapeutic systems.
Because of the molecular weight dependent adhesion capacity on skin both of the polyisobutylenes and of the amorphous poly-a-olefins, the adhesive properties of the system of the invention may be adjusted within a very wide range without having to alter the chemistry of the base components. Often, a slight variation in the percentage proportions of the basic components is enough to give desired product properties.
This aspect is very important especially within drug development. The careful selection of unobjectionable raw materials possessing good skin compatibility is costly and time consuming. It is therefore desirable to be able to make specific adjustments to product properties by varying the percentage composition of the known raw materials, thereby obviating the time consuming replacement of a complete raw material.

Active substance patch, kind to the skin, for transdermal administration of nonsteroidal antirheumatics

Abstract: b) from 5 to 40% by weight of amorphous poly-xcex1-olefin,

Abstract: c) from 10 to 60% by weight of an insoluble hydrophilic filler having an average particle size of less than 100 xcexcm, and


A delivery device including a) a housing, b) a container for a fluid arranged in the housing, the container having an opening, c) a delivery conduit connected in fluid communication with the opening, the conduit having a front end in flow respect distal from the container and a rear end in flow respect proximal to the container, the front end and the rear end defining an axis therebetween and a forward direction and a rearward direction, and d) a pump arranged to deliver fluid at least in a direction from the container through the conduit, the device comprising, a sensor able to change state in at least one respect in response to a predetermined proximity of an object to the sensor in a sensing direction, a converter, separate from or integral with the sensor, converting at least one of the sensor states into an electromagnetic signal, and a processor, receiving the electromagnetic signal and delivering a control signal to an operational component of the device.

The present invention relates to a delivery device including a) a housing, b) a container for a fluid arranged in the housing, the container having an opening, c) a delivery conduit connected in fluid communication with the opening, the conduit having a front end in flow respect distal from the container and a rear end in flow respect proximal to the container, the front end and the rear end defining an axis therebetween and a forward direction and a rearward direction, and d) a pump arranged to deliver fluid at least in a direction from the container through the conduit. The invention also relates to a method for operation such a device.
Although delivery devices are known for use in a vast variety of applications the present invention is mainly concerned with injection devices in applications where the injection receiving object is solid or semi-solid and wherein the orientation of the injection device relative the injection receiving object is critical to the proper outcome of the injection. Typical applications are the administration of pharmaceutical preparations to humans or animals where orientation is important for diverse reasons. Depending on the nature of the preparation and the intention of the treatment the target tissue is vital for correct biochemical activity, availability and absorbency period. The intended injection site may for example be subcutaneous, intramuscular or intravenous. The dose delivered is often critical and erroneous treatment may result both from lost preparation due to e.g. inadvertent needle release or partial placement in wrong tissue. Conversely, especially larger volumes may intentionally be distributed at several depth during needle penetration or partially in slow releasing tissue and partially in fast releasing tissue.
These demands can be met also when using the simplest injection devices, such as the common hypodermic syringe, when in the hands of a skilled operator who also may initiate medically relevant corrective measures in case of accidents and malfunction. More or less automated devices has since long existed to enable laymen with limited training performing injections with reasonable safety in critical or emergency situations. Often the devices are designed for single shots only. A general trend in long-term medication is to place the administration responsibility on the patient himself, also in the case of child or disabled persons. Here the demands are still higher. The continuous medication requires the patient to cope with repeated dosing, perhaps with varying dose setting and proper replacement of emptied cartridges with fresh ones as in pen-type injectors. A high degree of automation and control is desirable to avoid mistakes, not only at the mere injections steps but also the critical initiation and preparation steps. Patients dependent on daily administrations also have a legitimate need for convenience and devices discrete enough to be brought around in daily life.
Mechanical automation is provided in common autoinjectors. Typically the user is expected to position the device in proper injection orientation against the skin and operate a trigger button. Stored mechanical energy, e.g. in a spring system, may then perform autopenetration into the tissue, autoinjection of the medical and possibly also automatic needle retraction. Simpler systems may not provide autopenetration but assume the user to make the needle insertion. Hence the devices give the operator little assistance in orienting and localizing the devices in respect to the body. Autoinjectors are also known that require the operator to press the device against the injection site in order to trigger the injector. Typical examples are disclosed in AU 563.551, U.S. Pat. No. 4,717,384, EP 518.416 and WO 93/23110. The help provided by such constructions is limited and inflexible and cannot be adapted for different foreseeable operational or hazardous situations. Pressure rather than position based triggering makes desirable adaptations still more difficult Generally, once triggering has occurred, either intentionally or inadvertently, the operation sequence proceeds irreversibly. Moreover, the dislocation risks are generally high in mechanical devices due to rebound effects and the forced transitions involved.
Automated devices based on electronic or electromechanical principles have also been proposed. Disregarding here infusion pumps and similar injection devices for primarily hospital or permanent use, where device orientation generally is not critical, several prior patent specifications, as represented by e.g. EP 143.895, EP 293.958, DE 2.710.433, WO 93/02720, WO 95/24233 and WO 97/14459 as well as our copending applications SE 9602610-9 (U.S. Pat. No. 60/021,397) and SE 9602611-7 (U.S. Pat. No. 60/021,293), relates to hand held devices for direct action against the body. The known devices take advantage of automation principles in several respects, such as the precise and reproducible injection possible with electric motors, motor assisted autopenetration and mixing or reconstitution, cartridge identification, sample analysis, injection data collection and manipulation, dose setting, injector orientation relative gravity for proper mixing or deaeration etc. In spite of this diversity the automated devices in this class do not deal with device orientation versus the injection receiving body and do not solve any problem relating thereto.
Accordingly there is a continuing need for injection devices assisting the user in device orientation related handling steps and preventing or ameliorate consequences of mistakes and misuse resulting therefrom, especially useful for patients under self-administration. Although the present invention has a more general utility, it will mainly be described against this background.
A main object of the present invention is to avoid the disadvantages and shortcoming of known injection devices as described. A more specific object is to provide an injector assisting the user in proper orientation of the device in relation to the injection site. Another object is to provide a device being flexible and adaptable to different handling and operation situations. Still another object is to prevent or ameliorate consequences of unintended actions or misuse. Another object is to facilitate administration of the preparation in the correct target tissue. Yet another object is to avoid irreversible injection procedures. A further object is to avoid dependence on purely mechanical orientation means. Still another object is to offer orientation assisting means fully compatible with electronic or electromechanical automation means. Yet another object is to provide such devices with high simplicity in handling and suitable for patient self-administration or otherwise requiring limited skill and training.
These objects are reached with a device and method having the characteristics set forth in the appended claims.
By providing an injection device with a proximity sensor and a converter to derive an electromagnetic signal from the sensor several of the abovesaid objects are reached. The signal is immediately available for and compatible with any other electronic or electromechanical automation means present on the injector and reliance on purely mechanical orientation means is avoided. The signal can be recovered without requirements for pressure or high forces. Use of the transformed sensor output is highly flexible and can be adapted to a multitude of operation situations. If used in the device triggering sequence, inadvertent initiation can be avoided by requiring a predetermined characteristic to be present, such as a sustained or repeated signal, or making the signal operable only within a narrow sequence window. Similarly, irreversible operation procedures can be avoided by using the sensor output also for device disabling purposes, for example to stop an injection if the device is moved to an improper position. For similar reasons the device can be made selective in respect of target tissue by allowing injection only at predetermined penetration depths. Manipulation mistakes can be prevented if the signal is used to warn or alert the user before given displacement tolerances have been passed. The total handling relieves available serve to make the device excellently suited for applications where simplicity is vital, as in many cases of patient self-treatment. The principles used are compatible with most manual or automatic injection initiation, operation and termination steps and may for example be adapted to automatic penetration, injection and needle retraction, when present. The device itself need not be more complex than necessitated by other considerations, especially not when using existing parts, such as a needle cover, also for the sensing purposes.
Further objects and advantages with the invention will be evident from the detailed description hereinbelow.
As indicated in the introduction the injector described herein may be used for a variety of purposes within and beyond the medical area and for any type of preparations, such as chemicals, compositions or mixtures, in any container and delivered for any purpose. For reasons outlined the system has certain special values in connection with medical delivery devices where also the design constraints are more severe than in most other applications. For convenience the invention will be described in terms of this application.
The principles of the present invention may be used for delivery devices or systems in broad terms. The delivery conduit from the device may be an infusion channel or any conducting means such as a tube or catheter, a needle or cannula or a needle-less system based on liquid jet or a particle gun with gas propellant. The container content material shall be deliverable by use of a delivery mechanism, also referred to herein as a pump, and any material fulfilling this requirement can be used. Normally the material is a fluid and preferably a liquid, including materials behaving as liquids such as emulsions or suspensions. These observations relates to the final preparation whereas other components, notably solids, may be present before final preparation. The nature of container content shall also be understood to include medical in broad terms and to embrace for example natural components and body fluids prefilled or drawn into the container although most commonly the medical is factory prepared. The invention may assist in solving special problems in connection with sensitive compounds susceptible to degradation or denaturation under mechanical stress such as high shear forces. Compounds of high molecular weight may be of this type, high molecular weight hormones for example growth hormones or prostaglandins. The invention may also assist in solving special problems in connection with medical requiring a preparation step immediately prior to the infusion, typically a mixing of two or more components, which all may be fluid or may include a solid as when dissolving a lyophilized powder in a solvent, such as hormones or prostaglandins.
The administration manner can also be varied within broad limits and may include entirely continuous infusion, continuous infusion with varying flow or intermittent infusions or injections with repeated either equal or varying doses. Especially when combined with automation means in a preferred way the administration manner can easily be varied by adaptations in software or similar control. In portable devices the intermittent administration is common. Similarly, although delivery devices may be contemplated also for a single dosing operation, generally they are designed for more than one or multiple individual doses for intermittent administration.
In addition to the basic functions for delivery purposes the delivery system with preference may include other valuable features such as for initiating the container and its content and provide various checks and controls of both the container and the pump part electronics and mechanics.
The invention may be applied to delivery devices in stationary or permanent set-ups. For reasons to be explained the invention give special advantages in delivery devices for ambulatory purposes, especially those being autonomous with on-board energy storage, motor and processor means and in particular small hand-held devices of truly portable nature.
As said in the introduction a preferred delivery device can be said to generally comprise at least a) a housing, b) a container, c) a delivery conduit connected in fluid communication with the container and d) a pump arranged to deliver fluid at least from the container through the conduit.
The device housing shall be understood in general terms and mainly represents the point of reference, unless otherwise indicated, for movements and also the point of reference for forces applied by actuating means performing said movements, whereat the force is applied between the housing and the moving or gripped part. Movable parts may be present in the pump arrangements or e.g. in parts performing mixing, autopenetration, needle ejection and retraction etc. The minimum functional requirement is that the housing offers a support or platform for the movable parts and the actuating means providing the movements and forces. As in common practice, however, it is preferred that the housing forms a container at least partly embracing the parts and preferably also to such an extent that only the features designed to be controlled or monitored by the operator are externally exposed.
The container part shall be understood in broad sense and may take a variety of forms such as any kind of tube, vessel, flexible bag, vial, ampoule, cartridge, carpoule, syringe body etc. There are some advantages in using containers that are rigid, at least at its opening or the part for attachment to the mechanism but preferably generally rigid, such as vials, ampoules or syringe bodies. Common container materials such as glass or plastic can with preference be used. The container may be an integral or composite structure, such as including an outer casing or any other multipart construction for closures, fixtures, protection etc., and whenever used herein xe2x80x9ccontainerxe2x80x9d shall be understood to include any auxiliary part present. The container may be integral with the housing, e.g. for use in disposable injectors, when the container is refillable or when the container is part of the pumping system repeatedly drawing the preparation to be injected from an external source or channel before each injection stroke. The container may also be separate, e.g. for allowing replacement in case of disposable prefilled containers, for simple sterilization or scrapping in case of change of content type or patient. As known per se more than one container may be present, e.g. in case it is desirable to perform a mixing before injection, mixing during injection when drawing a part volume from each container or in case of sequential injection of different components.
The container has at least one opening through which the medication pass during the main delivery operation of the device, either from the container interior to the surrounding for e.g. administration of the medical to the patient or to the container in case of aspiration of body fluids or at preparation steps such as filling, mixing or dissolution in the container, during which operations the opening need to be present. It is possible and even in many situations preferred that certain device operations, such as initiation, takes place before communication has been established and the opening requirement shall then be considered satisfied by the preparation means for creating the communication such as the presence of a removable closure or a pierceable or rupturable part on the container itself as in the case of an ampoule or bag or a specially designed part as in case of penetrable membranes or septum. All communication may take place through one opening, for example both medical passage and pressure equalization in a rigid container or by delivery from a container which is flexible or has a movable or deformable part but nothing prevents that further openings are provided for similar purposes, which can be identical to the at least one opening but which can be entirely different and for example be adapted for another purpose of e.g. infusion or syringe type with a movable wall or piston.
The container may be a simple bottle, vial or bag in case the delivery device is arranged to withdraw, continuously or intermittently, metered amounts therefrom for delivery as defined. Often, and especially in connection with self-administration, the container type is more elaborate and is commonly in the form of a cartridge, being the container part of a syringe type of delivery system, which may be still more elaborate in the case of multichamber cartridges. A cartridge for the present purposes may generally be said to include a vessel having a front part and a rear part defining a general cartridge axis, an outlet for the preparation arranged at the front part and at least one movable wall arranged at the rear part, a displacement of which wall causes the preparation to be moved towards or expelled through the outlet. Vessel shape and movable wall have to be mutually adapted. The vessel may have a substantially constant internal cross-section, with a similarly constant vessel axis, between front and rear parts giving a generally tube-shaped vessel, and most preferably the cross-section is of the common circular type giving a substantially cylindrical vessel. The movable wall is then preferably a substantially shape-permanent, although possibly elastic, body sealingly adapted to the internal vessel surface and preferably of the piston type.
Dual or multi chamber cartridge types are known e.g. for preparations demanding a mixing of two or more components or precursors before administration. The components are kept separated by one or more intermediate walls of different known designs, which walls divide the vessel into several chambers, sometimes placed parallel along cartridge axis but most commonly in stacked relationship along the axis. Unification of the components may take place by breaking, penetrating or opening a valve construction in the intermediate walls, for example by introducing a pin or needle through the cartridge front, through or at the rear movable wall or by means at the cartridge exterior (compare e.g. the cited WO 93/02720). In another known design the intermediate wall or walls are of the plunger type and flow communication between the chambers is accomplished by moving the plunger to a by-pass section where the interior wall has one or several enlarged sections or repeated circumferential grooves and lands in a manner allowing by-flow of rear chamber content into front chamber at displacement of the rear movable wall (compare e.g. U.S. Pat. No. 4,968,299 or WO 93/20868 and WO 95/11051). The chambers may contain gas, liquid or solids. Generally at least one liquid is present. Most commonly in pharmaceutical applications only two chambers are present and typically contains one liquid and one solid, the latter being dissolved and reconstituted during the mixing operation.
In general terms the delivery conduit is connected in fluid communication with the opening of the container and has a front end in flow respect distal from the container and a rear end in flow respect proximal to the container. In its most basic form the conduit can be seen as a continuation of the container opening. In this sense the front end may be of any nature including an connection to another conduit, e.g. any of the common infusion channels mentioned. It is preferred, however, that the front end is the termination of an injection channel adapted for delivery of the preparation to the target site, e.g. on or in the patient, for which purpose at least the last, frontmost, part of the conduit should be suitable for delivery to the site. Depending on the delivery mechanism used the front end may not be designed for direct contact with the target site, as in case of liquid jets, powder guns or sprays, where the front end may be an orifice or nozzle for positioning at a distance from the target or on the surface of the target in spite of that the true target is below the surface. In other instances the front end is designed for penetrating into the target as in case of cannulas or common needles. The channel between the front end and the rear end may be curved or bent, as for a flexible infusion tube or in an on-board permanent connection, although in many applications it is desirable that the conduit is substantially straight, as for a needle on a syringe. Generally at least the last, frontmost, part of the conduit defines in flow sense an exit axis and a forward direction and a rearward direction. Positional and directional statements will be given in relation hereto unless otherwise indicated
The mechanism for delivery of medical through the container opening should basically include at least one type of pump which may have to be selected for the special kind or container and medical used. The pump may include any kind of pressure source, such as mechanical or electrolytic pressure build-up, in the container and suitable valve means for control, which method can be used with virtually any kind of container and any kind of product, such as transdermal delivery of powder, as exemplified by WO 94/24263, similar delivery through liquid jets, as exemplified by WO 94/2188, or regular tube infusion, as exemplified by WO 88/09187. Any kind of container can also be used with pumps based on peristaltic action or centrifugal action, although also for general use pumps based on controlled positive displacement are preferred and especially such pumps based on a separate cylinder and piston action, as exemplified by U.S. Pat. No. 5,480,381 for liquid jet or U.S. Pat. No. 4,564,360 for a manually operated needle based device. The common syringe type container need a specialized pump system. Either the mechanism is adapted to act on complete syringes, having their own piston rods, by engaging and axially displacing said rod, as exemplified by the initially referenced U.S. Pat. No. 4,978,335, which may be preferred when it is desired to accommodate syringes of many different types and sizes, or the mechanism has a piston rod acting more or less directly on the piston of a cartridge type container, as exemplified by WO 95/26211, EP 143.895 or EP 293.958, which can be made smaller and more adapted to portable devices. Also dual or multiple chamber cartridges can use a similar devices for its various phases, as exemplified by the initially mentioned WO 93/02720. Although the various pump mechanisms discussed may include mechanical means for affecting the medical or a piston the means, such as a piston rod, may be actuated by any known means, such as gas pressure, vacuum, hydraulics, springs or manual operation. It is preferred to actuate the pump mechanism by electric devices such as an electrical motor, indirectly or preferably directly, among others because of its ease of adaptation to an overall automated device.
The mechanism may preferably include further components. The mechanism may for example include special means for securing doses delivered, e.g. by direct metering of medical delivered, although it is generally preferred to utilize directly or indirectly the pump for this, e.g. by monitoring axial displacement or the rotation of a piston rod axis in a manner known per se. In particular it is preferred that the mechanism includes a control system operative to perform at least part of the abovementioned administrative patterns, initiation of containers or cartridges, self-control or surveillance and possible recording of operation steps conducted. Such systems are known in the art, as exemplified by U.S. Pat. No. 4,529,401, and may be designed in a multitude of ways. For the purposes of the present invention it is preferred that the control system drives and monitors at least part of the sensor system and processes data obtained therefrom.
The principles of the present invention may be utilized in connection with any injector whenever it is desirable to establish distance or orientation between any of its part and an object. The object may be the operator, e.g. to disable the device unless presence of an operator is positively verified. The object may be communication link part, e.g. in order to secure proper transmission in case of data exchange.
In accordance with a main purpose, of securing a proper position, the object is the injection target, e.g. the patient or animal to receive the delivered or injected preparation. In order to accomplish this feat it is preferred that the sensor is positioned so that its position relative the conduit front end is given. In case the conduit front end is not given in relation the housing, as when using a flexible tube conduit, this may require that the sensor is arranged fixed in relation to the front end to assist the user in localizing this end. This arrangement may also require a wire or other communication link to the housing in case the signal is to be used or processed by automation means in the housing. There are advantages in using the invention in connection with injection devices with given spatial relationship between conduit front end and the housing. The conduit may still be movable in relation to the housing, e.g. with needle exposure and retraction as is common in autoinjectors or simply for accessing the needle or its cover or adjusting penetration depth, but is then normally guided in a predetermined and foreseeable way. In these cases of conduit front end arrangement on the housing the sensor can be arranged at said conduit front end. Preferably the sensor is fixed in relation to the housing. The invention has with success been utilized in connection with needle based injectors where location is critical for reasons discussed in the introduction. The sensor positions given here shall not exclude that the sensor itself comprises movable parts as in the case of a switch.
Sensing direction in relation to the injection target depends on the purpose for the device positioning and the sensing direction can be entirely independent of delivery or injection direction, e.g. in the injection in the injection independent situations indicated above. Also when the desired device orientation is related to the injection direction the sensing direction may be different from the injection direction, e.g. normal or reverse thereto, for example if there is a reference surface other than the injection target surface as when working in a body cavity or relative a fixture. In less complicated situations it is preferred that the sensing direction has at least a component parallel to the injection direction, or to the conduit axis at the front end as defined. A sensing direction in an angle to the injection direction, especially an acute angle, may be used, e.g. to secure a proper starting position when inserting a needle laterally or sloping towards the target surface as is common when introducing a needle or cannula a certain safe distance although to a limited depth or when body access does not allow more perpendicular approach as in dental applications. In most applications it is preferred to make the sensing direction substantially parallel with the injection direction.
Sensor type selection may be dictated by numerous circumstances such as the purpose of sensing, the object nature and target type, further signal processing, space consideration, energy available etc. Generally suitable sensing principles and components are known and can be used as such or with design adaptations for the present purposes.
It may be desirable to use contact-free sensors able to detect the presence of or proximity to an object also with the sensor at a distance from the object, e.g. to allow a free positioning with respect to other device parts and constraints, to maintain operation access in limited spaces, to prevent sensor contamination, to protect a fragile sensor from damages, to adapt sensing to an otherwise contact-free injector type of for example liquid jet or powder gun type etc. Sensor types for this purpose may be based on for example heat, IR, or radio sensing. Common components can be used such as, but not limited to, thermistors, thermoresistors, IR-receivers etc., which components as such, or the electronic circuits connected thereto, may be tuned for a certain target temperature, e.g. body surface temperature. When including a transmitter, e.g. radio, IR or ultrasound, a receiver can be set to give a signal at a certain distance based on amplitude, frequency, phase or shielding affected by the target. A preferred method being capacitive or inductive sensing, which is simple, reliable and adaptable to both target type and distance. The desired signal may be derived from a change in capacity or electromagnetic field when influenced by the target. All the methods mentioned are able to detect the presence of an object by change in the corresponding parameter and also to provide the desirable electromagnetic signal necessary by use of existing and commercial components. Nothing excludes that the device also incorporates parts to be in contact with the object, e.g. a sleeve or any other spacer structure for the purpose of assisting in stabilizing the device during injection, which structure in this case need not be arranged to provide the proximity signal. When desirable the abovementioned sensor types can also be used in direct contact with the object, either to obviate the need for the additional structures or to provide additional contact assistance.
Contact between injector and object is necessary when the preparation is to be introduced into the object through a channel such as a needle, cannula or infusion tube. As indicated in many situations it is desirable to have additional contact between injector and object, e.g. to stabilize the device during injection, to relieve the operator by resting the device on or even attaching the device to the object, to compress or stretch the skin of a patient at the injection site, to distract the patient from the penetration pain etc. Any of the above mentioned proximity sensors operational at a distance can be used also in contact with the object, with or without a protruding member as described. In case of contact, however, the sensor with preference can be made in the form of a contact sensor. The mechanical contact can be sensed for example as the pressure exerted between sensor and object when the parts have the desired predetermined relative positions, which method may also be adapted to respond only when a certain predetermined contact pressure is present, e.g. for proper injection or as a safeguard against recoil forces. The sensor may comprise a true pressure transducer, a piezoelectric device or a switch biased with for example mechanical means, such as a spring force or a yielding snap type lock. Pressure sensing need not involve large movements in any sensor component. Contact may alternatively be sensed as the displacement of a movable part caused by the object at relative movement therebetween. Displacement sensing can be made simple and require only low forces. The displacement in turn may be registered as such, e.g. as a current induced in a coil by the movement, which additionally may provide a speed signal. The displacement may also be registered as the location of the movable part when in the critical position, which can be done with any of the pressure detector as mentioned but a switch type detector may be sufficient. Any switch type can be used, for example based on optical detection, e.g. by a photoelectric element or IR transmitter and receiver, of the movable part in the critical position. Conventional mechanical switches can be used having movable contact surfaces, e.g. standard microswitches or application specific designs with contact means open or closed by the movable part. For reliability reasons it is preferred to use switch elements indirectly affected in the switching position, e.g. Hall elements or tongue elements affected by a magnet or relay elements affected by an induced current from a movement, and especially those being encapsulated. The displacement may be give a signal only in the desired end position, which is sufficient for many purposes, but may also provide signals along the path, either continuously or at multiple discrete locations, e.g. to monitor proper use of the device or when providing adjustable proximity sensing. The displacement of the movable part is typically larger than in pressure sensing, say at least 1 mm, preferably at least 2 mm and most preferably at least 4 mm.
Independent of sensor type used the sensor may be provided on the delivery device as an additional component over those required for other purposes. It is preferred, however, to adapt structures for other purposes an additional sensing capability, which is most easily done with contact sensors. It is often preferred to arrange the sensor with a part associated with the device conduit. In case of contact free delivery, as in liquid jets, powder guns, sprays, inhalators etc., such devices often comprise a guiding or orienting part for contact with the object, such as a sleeve or orifice type opening for more general use or a part adapted to the specific target organ, such as mouthpiece, an eyecup etc., and it may desirable to associate the sensor with such parts. Similar parts may be present and utilized also when using delivery devices having conduits for contact with the object but here with preference the sensor may be associated with these conduit component, e.g. incorporating tubes, needles or cannulas. Often a movable cover is used over a tipped conduit for insertion into an object, which cover is pushed rearwards in connection with conduit insertion. The cover may be present to protect the conduit against damage or contamination, to protect the user from inadvertent pricking or to hide for example a needle from a patient to reduce anxiety. The sensor can with advantage be associated with such a cover so that the sensor in some way gives a signal in response to movement of the cover and preferably so that a distinguishable signal is received at proper penetration of the conduit. This principle can be used in connection with a flexible infusion tube if a cover is present, which is not always the case as infusion tubes are often inserted by skilled practitioners without need for assisting devices. Rather the advantages are most pronounced when the housing is gripped and used for conduit penetration, which is commonly the case at patient self-administration and which normally requires that the conduit is arranged fixed in relation to the housing in at least all directions but axial, where a mobility may be retained for e.g. autopenetration or needle protector removal, but in many instances the conduit is fixed also in the axial direction. The invention has been utilized with advantage with a sensor associated with a movable needle cover for an injector.
In all sensor arrangements described the sensor should be positioned so that a detectable signal change is obtained when the critical device part, forming a reference point, has the desired location in relation to the target object. In cases of non-contact between conduit and object this may be a distance suitable for delivery of the preparation, either a concentrated delivery for penetration as for a liquid jet or a distributed delivery as for a spray. The sensor may be a pressure sensor for a part placed against the object in the suitable position or a displacement sensor on for example a cover uncovering an orifice or a simple front switch. For penetrating conduits the sensor may be a pressure sensor placed so as to be engaged by the object at the predetermined penetration depth e.g. at the base of a needle or cannula, or a displacement sensor for a cover as described with a signal change at a predetermined displacement of the cover e.g. by a switch at the desired point.
As earlier indicated a sensor measuring direction may be in any desired angle although normally in the forward direction with respect to the conduit. A single sensor direction may be sufficient in most application although use of more sensors can be used to fix the position in other dimensions, e.g. two sensors to determine orientation in a given plane or three sensor to determine orientation in all three dimensions, for example when operating the device in a cavity.
The signal received from the sensor shall be in the form of, or transformed into, an electromagnetic signal representative for the proximity data as described. The electromagnetic signal may be based on electromagnetic radiation, such as an optical signal, but is preferably an electric signal. Many suitable components for use as sensors are designed to give such a signal output but may otherwise be inserted in a circuit securing such an output. Any inherent, integral or separate arrangements of this kind can be regarded as a converter for sensor output into the electromagnetic signal. The electromagnetic signal so received or transformed is in general terms processed in a processor to deliver a control signal. The control signal in turn is used to control a functional or operational component of the device. The operational components can be of any kind although some typical examples will be given below. The control signal can be of any nature, such as mechanical, optical etc., depending on its further use but is preferably an electric signal.
The control signal may be used to issue a message to the user, e.g. to warn or alert the user of an improper position before the device is activated for delivery. The message may be a sound, a tactically sensible signal such a vibration, a visual signal in the form of a warning lamp or a more complicated message on a display etc. or any combination of such messages.
It is preferred that the control signal is used to control the basic device functions over the actions taken by the operator. The control signal may be used to enable or disable the device respectively, dependent on the proper proximity condition. The enabling/disabling may take place by an electromechanical link, such as a relay device blocking a mechanical function e.g. a piston rod or pump mechanism. Better is to use this function in connection with devices having at least some automation means for driving the device, such as an electric motor, the operation of which may be determined by the control signal. Still better is if the device further includes processor means for control of the motor means, e.g. in order to secure proper cartridge control, initiation, sequencing of actions, dosing, feedback of administration data etc. in which case the electromagnetic signal can be fed to the processor for further flexibility, e.g. allowing the processor to issue a motor activation control signal only when the proximity condition is fulfilled or only when the abovesaid initiation steps have been properly concluded or proper condition has been positively verified in a self-control program. An existing processor unit may here act as the processor between the electromechanical signal and the control signal.
The control signal may further be used to actually trigger the device, i.e. as soon as the sensor signals the predetermined proximity condition an automatic function starts. As for the enabling/disabling condition just described this triggering function can be used for purely mechanical driving means via an electromagnetic release mechanism, better together with electric motor means an most preferably with processor controlled automation in the device.
The operations actually enabled or triggered can be of various nature. Preferably at least the injection is affected, in multidose devices perhaps including mechanical but preferably electric control of the dose delivered. In autoinjector type devices the autopenetration step may also be affected, preferably so that the sequence of autopenetration and autoinjection is controlled, possibly with a final needle retraction step. Autoinjectors are known which either deliver preparation also during the penetration phase or enable the injection first at completed penetration and the invention is compatible with both modes of operation. In case of multichamber cartridges with overflow or by-pass arrangements, which are known as such, the injection procedure may incorporate injection of different preparations in sequence, such as an anesthetic followed by an active ingredient or an active component followed by an rinsing component.
If the critical proximity value is made adjustable, either electronically in the processor e.g. by selecting different electromagnetic signals from discrete or continuous outputs or mechanically e.g. by making the sensor movable relative the housing, the use flexibility further increases. The device can be adapted to different conduit characteristics, e.g. needle lengths, couplings and construction and to different injection depth, e.g. type of tissue such as subcutaneous, intravenous, fat or muscle. The device may also be adaptable to local object target site conditions, such as necessary local penetration depth for the target tissue type, which can be made manually by a skilled operator or automatically if the device in a manner known per se is equipped with means for distinguishing different target types, e.g. based on penetration force or injection pressure feedback.
If is preferred that the sensor delivers different distinguishable electromagnetic signals for different proximity values, again either a continuous signal from a non-contact sensor or a contact sensor with a displaceable member giving continuos or multiple discrete electromagnetic signal along its path. Now more advanced administration patterns can be assisted by the sensor, for example delivery of preprogrammed amounts, or components in case of multichamber devices, at different depths or a continuous spread of a larger volume over a range of penetration depths.
The sensor electromagnetic signal may with preference be analyzed by the processor not only in respect of absolute distance value but also in respect of the change of said distance value over time in order to provide additional valuable information. If combined with a given penetration force or injection backpressure force the data may be indicative of the object nature, e.g. tissue type, or of misuse e.g. a stroke or hit rather than proper penetration or a way for guiding the user to such a predetermined suitable insertion speed.
All of the above applications of the sensor signal are facilitated by the presence of at lest some electromechanical means in the device to be further described hereinbelow.
Generally for full utility the device should be combined with suitable electronics to drive the active elements of the sensor and to extract the electromagnetic signal therefrom. The processor electronics should at least be able to detect the sensor output, either for extraction of continuous or discrete data and put it to use via the control signal, e.g. in any of the manners exemplified, for which purposes the processor may at least adapt and/or transmit the electromagnetic signal to an operational component. Preferred signal processing will be exemplified below.
The electromagnetic signal from the sensor may be a simple single on/off signal, as received from a switch type sensor component, and can be sufficient for many purposes e.g. a plain triggering or enabling command. A quasi-continuous signal may be received from e.g. multiple on/off switches for example along a displacement path or levels of mechanical pressure resistance. A true continuous signal may be received from may sensors such as the noncontact types mentioned, from pressure transducers, piezoelectric devices or drossel and magnet based motion sensors. Examples for use of these responses have been given under preceding headings.
A simple on/off signal can be used as such a switch in e.g. simple motor enabling circuit or as an analogue but preferably digital input signal in a more sophisticated processing for automation or control. A quasi-continuous signal may be used similarly of each of the multiple switches has independent circuitry to enable distinction therebetween or as a continuous signal having a frequency of on/off pulses if the switches are arranged in parallel. A truly continuous signal contains still more information and can be treated in another way than the on/off signal.
Although all of the signal types may be used in a simple manner there are some advantages in using the signal in a more sophisticated manner. Firstly, more user information may be extracted from the signal. Secondly, signal information may be used to compensate for random factors in the device response to extract a more reliable treated signal. Thirdly, previous hardware feature may be replaced by software e.g. to permit a smaller or simpler device.
Accordingly the sensor output may be monitored for its signal, e.g. amplitude, versus a variable function, directly or indirectly, and the function processed before an activity is based thereon. The variable may be distance, forming an signal versus distance function, e.g. when a movement as such is to be monitored, but the variable is preferably time, forming an signal versus time function. The function obtained may be treated as continuous but it is preferred that values are sampled from the device output, which may be made at irregular but preferably at regular time intervals at a certain frequency. Sampling can be in any of several known ways. The sampling may be digital in the sense that the amplitude is compared with a reference level and either set to a binary 1 or a binary 0 depending on whether the amplitude is above or below the reference level, which may be varying but preferably is fixed. Among others for extracting more information from the raw data an analog sampling method is generally preferred, in which the function absolute amplitude value is repeatedly registered. The analog value can be processed in an analog processor but it is mostly preferred to convert the value to digital form and process it in a digital processor. The signal may in a manner known per se be filtered to remove certain frequency ranges or noise.
The function values may be memorized and processed at any time and rate but real time processing is generally preferred in most applications, which may still require some memorizing of the values to be simultaneously processed at any given time. It is preferred that the processing involves at least two, preferably three and most preferably a multiple of function values at a time. Processing may take place in any known kind of analog or digital processor, preferably comprising a microprocessor such as a standard microprocessor or an application specific integrated circuit.
The processing may be operative to extract any kind of positional versus time information for recording or immediate action for any of the purposes exemplified. It is preferred, however, that the processing additionally serve to modify the raw signal from the device to make it more reliable for its intended purpose, some of which modifications will be exemplified.
The processing may perform an analogue to a physical dampening of the device or sensor movement. In continuous rest positions this may be achieved for example by filtering out certain frequencies, averaging out movements around an equilibrium point or extrapolating a regression curve. In discrete rest positions a similar result may be based on delayed or repeated check for amplitudes corresponding to a position corresponding to a stable rest position.
The processing may perform calibration of the device, for example by recording the actual device output at defined conditions, either staticly e.g. for discrete positions, or dynamically for continuous movements, and/or device response to various disturbances for example in respect of changes on driving conditions, ambient conditions etc.
The processing may perform an analogue to provision of physical hysteresis for device movements for example by requiring a certain degree of amplitude alteration for emitting a signal corresponding to a change from one position to another, e.g. to suppress frequent flipping around an equilibrium point.
Independent of which signal processing principles are applied there are some capabilities of special value in the present context. Contrary to mechanical solutions the signal processing should preferably provide some kind or reversibility in operation, i.e. after triggering an operation sequence, perhaps based on the sensor condition, the sequence should be possible to influence by a prescribed signal condition from the sensor. If for example the sensor signal indicates that the position is not any longer suitable for the current operation phase, such as penetration or injection, the device should be able to at least issue a control signal alerting and enabling the user to perform corrective measures, preferably also halt the operation phase in abidance of completed correction, and preferably also a recalculation or reprogramming of the processor means to deliver a complementary dose or additional dose, perhaps dependent on the coming time delay, at the following injection.
Convenient use of a reversibility capability would also benefit from the abovesaid hysteresis feature, i.e. the device should allow for some tolerances between enabling and disabling or operation and reversal. This feature can be provided by signal processing means as above exemplified but also by sensor design e.g. by giving a switch type sensor contact surfaces of the desired length or a bi-stable switch a mechanical bias having a certain inactive pressure range.
Preferably the device is also equipped with automation or processor means responsive to the sensor output only at a predetermined window in the operational sequence, e.g. after proper cartridge identification, mixing, deaeration, delay, dose setting etc. The means may also be responsive to a sensor output fulfilling certain characteristic criteria, e.g. speed of change, sustained stable change or repetition of change, to distinguish between proper condition and improper, inadvertent or accidental affirmance.
The sensor system of the present invention may give advantages also in entirely manually operated delivery devices or in mechanically driven devices, such as with manually cocked spring systems, for example when the sensor signal is used for alarm, indication and signaling purposes. As has been indicated it is preferred that sensor signal is used in automated devices for which purpose the device should include actuating means comprising at least one electromechanical device with energy storing means, such as a battery, for driving purposes. The connection between the sensor and the electromechanical device can be of different kinds. The sensor signal can be a simple switch directly affecting the electromechanical device. In order to make the additional functions described possible a more complex connection may be needed, either a hard wired circuitry with discrete components or preferably a general processor means such as a general purpose microprocessor or an application specific integrated circuit.
The electromechanical device can be any device that can be affected by electrical means to give a mechanical force. The electromechanical device can be a relay or solenoid type device or preferably an electric motor. It is preferred that at least the pump mechanism is controlled or affected by the electromechanical means. With preference also other functions are controllable by electric means, penetration means with possible return means. For simplicity these additional capabilities may not need electromechanical driving means of their own but may be driven by mechanical means, such as springs, cocked manually or by simple electromechanical means. For highest flexibility, though, at least electromechanical release means e.g. solenoids, and possibly separate electrical motor means, should be present for such additional functions.

Automated delivery device and method for its operation